N-acyl pyrrolidines and drugs for the treatment or prevention of cholecystokinin and gastrin-related disorders

ABSTRACT

Compounds of formula I ##STR1## wherein the substituents are as defined herein, are disclosed as treatments for disorders linked to CCK and gastrin. Processes for preparing the compounds are also taught.

This application is a National Stage application of PCT/FR94/00008,filed Jan. 3, 1994, and published on Jul. 21, 1994, as WO 94/15914.

The present invention relates to derivatives of formula: ##STR2## totheir salts, to their preparation and to the medicaments containingthem.

In the formula (I),

R represents a hydrogen atom or an alkyl, cycloalkyl or phenylalkylradical or a phenyl radical optionally substituted by one or moresubstituents chosen from halogen atoms and alkyl and alkoxy radicals,

R₁ represents an alkyl radical containing 1 to 12 carbon atoms in astraight or branched chain and optionally mono- or polyunsaturated, acycloalkyl radical containing 3 to 12 carbon atoms and optionally mono-or polyunsaturated, a polycycloalkyl radical containing 6 to 12 carbonatoms and optionally mono- or polyunsaturated, a phenylalkyl radical inwhich the phenyl ring is optionally substituted (by one or moresubstituents chosen from alkyl or alkoxy radicals or halogen atoms), adiphenylalkyl radical, a cinnamyl radical, a pyridyl radical optionallysubstituted by one or more alkyl radicals, a furyl radical optionallysubstituted by one or more alkyl radicals, a thienyl radical optionallysubstituted by one or more alkyl radicals, a quinolyl radical optionallysubstituted by one or more alkyl radicals, a naphthyl radical optionallysubstituted by one or more alkyl radicals, an indolyl radical optionallysubstituted by one or more alkyl radicals or a phenyl radical optionallysubstituted by one or more substituents chosen from halogen atoms andalkyl, alkoxy, hydroxyl, nitro, amino, monoalkylamino, dialkylamino,alkoxycarbonyl, --CO--NR₇ R₈, --NH--CO--CH₃, trifluoromethyl ortrifluoromethoxy radicals,

R₂ represents a --(CH₂)_(n) --CO--R₆, --(CH₂)_(m) --O--CO--R"₆ or--(CH₂)_(m) --NR₉ R₁₀ chain, an oxazolinyl radical optionallysubstituted by one or more alkyl radicals or a 3-alkyloxadiazolylradical,

R₃ represents a hydrogen atom or an alkyl or cycloalkyl radical or aphenylalkyl radical optionally substituted by one or more substituentschosen from halogen atoms and alkyl and alkoxy radicals,

R₄ represents a hydrogen atom or an alkyl radical, R₅ represents aphenyl radical (optionally substituted by one or more substituentschosen from halogen atoms and alkyl, alkoxy and alkylthio radicals), anaphthyl radical, an indolyl radical, a quinolyl radical or aphenylamino radical in which the phenyl ring is optionally substitutedby one or more substituents chosen from halogen atoms and alkyl, alkoxy,alkylthio, trifluoromethyl, carboxyl, alkoxycarbonyl, hydroxyl, nitro,amino, acyl, cyano, sulphamoyl, carbamoyl, hydroxyiminoalkyl,alkoxyiminoalkyl, hydroxyaminocarbonyl, alkoxyaminocarbonyl,5-tetrazolyl, 5-tetrazolylalkyl, trifluoromethylsulphonamido,alkylsulphinyl, mono- or polyhydroxyalkyl, sulpho, --alk--O--CO--alk,--alk--COOX, --alk--O--alk, --alk'--COOX, --O--alk--COOX, --CH═CH--COOX,--CO--COOX, --alk--SO₃ H (in salt form), --CH═CH--alk', --C(═NOH)--COOX,--S--alk--COOX, --SO--alk--COOX, --SO₂ --alk--COOX, --O--CH₂--alk'--COOX, --CX═N--O--alk--COOX, --alk--N(OH)--CO--alk, --alk--SO₂ H,--SO₂ --NH--CO--R₁₁, --SO₂ --NH--SO₂ --R₁₁, --CO--NH--CO--R₁₁,--CO--NH--SO₂ --R₁₁, --B(OH)₂, --C(NH₂)═NOH, --SO₂ --NH--R₁₂,--CO--NH--R₁₂, ##STR3## or 2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylradicals,

R₆ represents a hydroxyl, alkoxy, cycloalkyloxy, cycloalkylalkyloxy,phenyl or --NR₉ R₁₀ radical,

R"₆ represents an alkoxy, cycloalkyloxy, cycloalkylalkyloxy, phenyl or--NR₉ R₁₀ radical,

R₇ represents a hydrogen atom or an alkyl radical, a phenylalkyl radicalor a phenyl radical optionally substituted by one or more substituentschosen from halogen atoms and alkyl, alkoxy and alkylthio radicals,

R₈ represents an alkyl radical, a phenylalkyl radical or a phenylradical optionally substituted by one or more substituents chosen fromhalogen atoms and alkyl, alkoxy and alkylthio radicals,

or else R₇ and R₈ form, with the nitrogen atom to which they areattached, a saturated or unsaturated, mono- or polycyclic heterocyclecontaining 4 to 9 carbon atoms and one or more hetero atoms (O, N) andoptionally substituted by one or more alkyl radicals,

R₉ represents a hydrogen atom or an alkyl radical, a cycloalkylalkylradical, a cycloalkyl radical, a phenylalkyl radical or a phenyl radicaloptionally substituted by one or more substituents chosen from halogenatoms and alkyl, alkoxy and alkylthio radicals,

R₁₀ represents an alkyl radical, a cycloalkylalkyl radical, a cycloalkylradical, a phenylalkyl radical or a phenyl radical optionallysubstituted by one or more substituents chosen from halogen atoms andalkyl, alkoxy and alkylthio radicals,

or else R₉ and R₁₀ form, together with the nitrogen atom to which theyare attached, a saturated or unsaturated, mono- or polycyclicheterocycle containing 4 to 9 carbon atoms and one or more hetero atoms(O, N, S) and optionally substituted by one or more alkyl radicals,

R₁₁ represents an alkyl radical, a cycloalkyl radical, a trifluoromethylradical or a phenyl radical optionally substituted by one or moresubstituents chosen from cyano, alkoxy, nitro or amino radicals andhalogen atoms,

R₁₂ represents a 5-tetrazolyl radical,

R₁₃ represents C═O or S═O,

R₁₄ represents 0 or C═O,

n is equal to 0, 1 or 2,

m is equal to 1 or 2,

X represents a hydrogen atom or an alkyl or phenylalkyl radical,

alk represents an alkyl or alkylene radical,

alk' represents a hydroxyalkyl, hydroxyalkylene,

alkoxyalkyl or alkoxyalkylene radical, it being understood that n isother than 0 when R and R₃ each represent a hydrogen atom and R₁represents a pyridyl radical optionally substituted by one or more alkylradicals, a furyl radical optionally substituted by one or more alkylradicals, a thienyl radical optionally substituted by one or more alkylradicals, a quinolyl radical optionally substituted by one or more alkylradicals, a naphthyl radical optionally substituted by one or more alkylradicals, an indolyl radical optionally substituted by one or more alkylradicals or a phenyl radical optionally substituted by one or moresubstituents chosen from halogen atoms and alkyl, alkoxy, hydroxyl,nitro, amino, monoalkylamino, dialkylamino, alkoxycarbonyl, --CO--NR₇R₈, --NH--CO--CH₃, trifluoromethyl or trifluoromethoxy radicals.

In the foregoing definitions and those which will be mentioned below,except when otherwise mentioned, the alkyl, alkylene and alkoxy radicalsand the alkyl, alkylene and alkoxy portions contain 1 to 4 carbon atomsin a straight or branched chain, the acyl radicals or portions contain 2to 4 carbon atoms and the cycloalkyl radicals and portions contain 3 to6 carbon atoms.

When R₁ represents an unsaturated alkyl radical, the latter ispreferably an isopropenyl radical.

When R₁ represents a cycloalkyl radical, the latter is preferably acyclohexyl radical.

When R₁ represents an unsaturated cycloalkyl radical, the latter ispreferably a tetrahydrophenyl, cyclopentadiene or dihydrophenyl radical.

When R₁ represents a polycycloalkyl radical, the latter is preferably anorbornyl or adamantyl radical.

When R₁ represents an unsaturated polycycloalkyl radical, the latter ispreferably a norbornenyl radical.

When R₇ and R₈ form, with the nitrogen atom to which they are attached,a heterocycle, the latter is preferably a piperidino ring optionallysubstituted by one or more alkyl radicals or a1,2,3,4-tetrahydroquinoline ring-system.

When R₉ and R₁₀ form, with the nitrogen atom to which they are attached,a heterocycle, the latter is preferably a piperidino,perhydro-1-azepinyl, 1,2,3,6-tetrahydro-1-pyridyl,1,2,3,4-tetrahydro-1-quinolyl, 1-pyrrolidinyl,1,2,3,4-tetrahydro-2-isoquinolyl, thiomorpholino or 1-indolinylring-system, it being possible for these ring-systems to be optionallysubstituted by at least one alkyl radical.

The compounds of formula (I) containing one or more asymmetric centreshave isomeric forms. These isomers also form part of the invention.

The compounds of formula (I) for which R₅ represents an optionallysubstituted phenylamino radical can be prepared by reacting a reactivederivative of carbamic acid, optionally obtained in situ by reacting areactive derivative of carbonic acid, chosen fromN,N'-carbonyldiimidazole, phosgene, diphosgene, triphosgene andp-nitrophenyl chloroformate, with a derivative of formula: ##STR4## inwhich R, R₁, R₂, R₃ and R₄ have the same meanings as in the formula (I),with an aniline in which the phenyl ring is optionally substituted byone or more substituents chosen from halogen atoms and alkyl, alkoxy,alkylthio, trifluoromethyl, carboxyl, alkoxycarbonyl, hydroxyl, nitro,amino, acyl, cyano, sulphamoyl, carbamoyl, hydroxyiminoalkyl,alkoxyiminoalkyl, hydroxyaminocarbonyl, alkoxyaminocarbonyl,5-tetrazolyl, 5-tetrazolylalkyl, trifluoromethylsulphonamido,alkylsulphinyl, mono- or polyhydroxyalkyl, sulpho, --alk--O--CO--alk,--alk--COOX, --alk--O--alk, --alk'--COOX, --O--alk--COOX, --CH═CH--COOX,--CO--COOX, --alk--SO₃ H (in salt form), --CH═CH--alk', --C(═NOH)--COOX,--S--alk--COOX, --SO--alk--COOX, --SO₂ --alk--COOX, --O--CH₂--alk'--COOX, --CX═N--O--alk--COOX, --alk--N(OH)--CO--alk, --alk--SO₂ H,--SO₂ --NH--CO--R₁₁, --SO₂ --NH--SO₂ --R₁₁, --CO--NH--CO--R₁₁,--CO--NH--SO₂ --R₁₁, --B(OH)₂, --C(NH₂)═NOH, --SO₂ --NH--R₁₂,--CO--NH--R₁₂, ##STR5## or 2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylradicals.

This reaction is generally carried out in an inert solvent such astetrahydrofuran, dimethylformamide, a chlorinated solvent (chloroform or1,2-dichloroethane, for example) or an aromatic solvent (benzene ortoluene, for example) or a mixture of these solvents, at a temperaturebetween 20° C. and the boiling point of the solvent.

The reactive derivative of carbamic acid can be obtained under the samesolvent and temperature conditions.

The derivatives of formula (II) can be obtained by deprotection of aderivative of formula: ##STR6## in which R, R₁, R₂, R₃ and R₄ have thesame meanings as in the formula (I).

This deprotection is preferably carried out by means ofiodotrimethylsilane or trifluoroacetic acid, in an inert solvent such asa chlorinated solvent (chloroform or 1,2-dichloroethane, for example) oracetonitrile, at a temperature between 15° and 40° C.

The derivatives of formula (III) for which R₂ represents a --(CH₂)_(n)--CO--R₆ chain and R₆ is not a hydroxyl radical can be obtained byreacting a derivative of formula: ##STR7## in which R, R₁ and R₃ havethe same meanings as in formula (I) and R₂ has the same meanings asabove, with an acid of formula: ##STR8## in which R₄ is defined as inthe formula (I).

This reaction is carried out in an inert solvent such as acetonitrile,tetrahydrofuran or a chlorinated solvent, in the presence of a peptidecondensing agent such as a carbodiimide (N,N'-dicyclohexylcarbodiimidefor example) or an alkyl chloroformate, at a temperature between 10° and40° C.

The derivatives of formula (V) can be obtained according to the usualmethods for protection of amino acids.

The derivatives of formula (IV) for which R₂ represents a --(CH₂)_(n)--CO--R₆ chain and n is equal to 1 or 2 can be obtained by adaptation ofthe methods described by S. ROSSET et al., Tetrahedron Lett., 32, 7521(1991); T. GALLAGHER et al., J. Chem. Soc. Perkin Trans. I, 2193 (1991)and J. F. W. KEANA, J. Org. Chem., 48, 2644 (1983).

The derivatives of formula (IV) for which R represents a hydrogen atomcan be obtained by reduction of the compounds of formula: ##STR9## inwhich R₁ and R₃ have the same meanings as in the formula (I) and R₂ hasthe same meanings as in the formula (IV).

This reduction is generally carried out by means of hydrogen, in thepresence of palladium on charcoal, in an inert solvent such as analcohol or ethyl acetate, or by means of sodium borohydride in analcohol, in the presence of an alkali metal carbonate, at a temperaturebetween 20° C. and the boiling point of the reaction mixture.

The derivatives of formula (VI) for which R₂ represents a --(CH₂)_(n)--CO--R₆ radical, n is equal to 0, R₆ is not a hydroxyl radical and R₃represents an alkyl, cycloalkyl or optionally substituted phenylalkylradical can be obtained by reaction of a corresponding derivative offormula (VI) for which R₃ represents a hydrogen atom with a derivativeof formula Hal-R₃ in which R₃ has the same meaning as above and Halrepresents a halogen atom and preferably an iodine atom.

This reaction is generally carried out in an inert solvent such astetrahydrofuran or ether, in the presence of a base such as sodiumhydride or the sodium or lithium salt of hexamethyldisilazane, at atemperature between -78° C. and the boiling point of the reactionmixture.

The derivatives of formula (VI) for which R₃ represents a hydrogen atomand R₂ represents a --(CH₂)_(n) --CO--R₆ radical, n is equal to 0 and R₆is not a hydroxyl radical can be obtained by deprotection anddehydration of a derivative of formula: ##STR10## in which formulae R₁has the same meanings as in the formula (I) and R₂ and R₃ have the samemeanings as above, or a mixture of these derivatives.

These deprotection and dehydration operations are generally carried outby means of trifluoroacetic acid or iodotrimethylsilane, in an inertsolvent such as a chlorinated solvent (dichloromethane for example), ata temperature in the region of 20° C.

The derivatives of formulae (VII) and (VIII) can be obtained by reactionof a derivative of formula:

    R.sub.1 --M                                                (IX)

in which R₁ has the same meanings as above and R₁ --M repesents anorganomagnesium or organolithium derivative or a cuprate, with aderivative of formula: ##STR11## in which R₂ and R₃ have the samemeanings as above.

This reaction is carried out in an inert solvent such as tetrahydrofuranat a temperature between -78° C. and -20° C.

The derivatives of formula (X) can be obtained by reacting di-tert-butyldicarbonate with a derivative of formula: ##STR12## in which R₂ and R₃have the same meanings as above.

This reaction is generally carried out in the presence of triethylamineor 4-dimethylaminopyridine, in a chlorinated solvent such asdichloromethane, at a temperature in the region of 20° C.

The derivatives of formula (XI) are available on the market or can beobtained by esterification or amidation of pyroglutamic acid accordingto the methods described by M. HOLLOSI et al., Acta Chim. (Budapest),71, 101 (1972); B. RIGO et al., J. Heterocycl. Chem., 25, 49 (1988); J.H. BILLMANN, J. L. RANDALL, J. Am. Chem. Soc., 66, 745 (1944); R. B.ANGIER, V. K. SMITH, J. Org. Chem., 21, 1540 (1956); J. C. SAUER, H.ADKINS, J. Am. Chem. Soc., 60, 402 (1938).

The derivatives of formula (IV) for which R represents an alkyl,cycloalkyl or phenylalkyl radical, or a phenyl radical optionallysubstituted by one or more substituents chosen from halogen atoms andalkyl and alkoxy radicals can be obtained by reaction of a correspondingderivative of formula (VI) with a derivative of formula:

    R--M                                                       (XII)

in which R has the same meanings as above and R--M represents anorganolithium or organomagnesium derivative.

This reaction is carried out in an inert solvent such as tetrahydrofuranor ether, in the presence of a Lewis acid such as boron trifluoride ortitanium tetrachloride, at a temperature between -78° C. and the boilingpoint of the reaction mixture.

The derivatives of formula (III) for which R₂ represents a --(CH₂)_(m)--O--CO--R"₆ chain can be obtained by reacting a derivative of formula:##STR13## in which R, R₁, R₃ and R₄ have the same meanings as in theformula (I) and R₁₉ represents a --(CH₂)_(m) --OH chain, with a halideof formula Hal--CO--R"₆ in which Hal represents a halogen atom, andpreferably chlorine, and R"₆ has the same meanings as in the formula(I).

This reaction is carried out in an inert solvent such as a chlorinatedsolvent, in the presence of a trialkylamine, at a temperature between20° C. and the boiling point of the reaction mixture.

The derivatives of formula (XIII) for which R₁₉ represents a --(CH₂)_(n)--OH chain can be obtained by reduction of a corresponding derivative offormula (III) for which R₂ represents a --CH₂)_(n) --CO--R₆ chain, n isequal to 0 or 1 and R₆ represents an alkoxy or a hydroxyl radical.

This reaction is carried out in an inert solvent such as an alcohol(methanol, ethanol or tert-butanol), tetrahydrofuran or a mixture ofthese solvents, in the presence of sodium borohydride or diborane, at atemperature between 20° C. and the boiling point of the reactionmixture.

The derivatives of formula (III ) for which R₂ represents a --(CH₂)_(m)--O--CO--R"₆ chain, R"₆ represents an --NR₉ R₁₀ radical and R₉represents a hydrogen atom can also be obtained by condensation of aderivative of formula (XIII) in which R₁₉ represents a --(CH₂)_(m) --OHchain with an isocyanate of formula R₁₀ NCO.

This reaction is carried out in an inert solvent such as a chlorinatedsolvent, tetrahydrofuran or dimethylformamide, optionally in thepresence of a catalytic amount of an alkali metal alkoxide, at atemperature between 20° C. and the boiling point of the reactionmixture.

The derivatives of formula (III) for which R₂ represents a --(CH₂)_(m)--NR₉ R₁₀ radical can be obtained by reacting an amine HNR₉ R₁₀, inwhich R₉ and R₁₀ have the same meanings as in the formula (I), with aderivative of formula (XIII) in which R₁₉ represents a --(CH₂)_(m)--O--SO₂ --CH₃ radical.

This reaction is generally carried out either in the presence of a largeexcess of amine at a temperature between 0° and 10° C. or, when thehydrochloride of the amine is used, in a chlorinated solvent in thepresence of a trialkylamine at a temperature between 20° C. and theboiling point of the reaction mixture.

The derivatives of formula (XIII) in which R₁₉ represents a --(CH₂)_(m)--O--SO₂ --CH₃ radical can be obtained by reaction of correspondingderivative of formula (XIII) for which R₁₉ represents a --(CH₂)_(m) --OHradical with methanesulphonyl chloride.

This reaction is generally carried out in an inert solvent such asacetonitrile or methylene chloride, in the presence of triethylamine, ata temperature between 0° C. and the boiling point of the reactionmixture.

The compounds of formula (III) for which R₂ represents a --(CH₂)_(n)--CO--R₆ radical and R₆ represents a hydroxyl radical can be obtained bysaponification of a corresponding derivative of formula (III) for whichR₆ represents an alkoxy radical.

This reaction is carried out in inert solvents such as tetrahydrofuran,methanol or dioxane and water, in the presence of a base such as sodiumhydroxide, potassium hydroxide or lithium hydroxide, at a temperaturebetween 0° and 25° C.

The derivatives of formula (III) for which R₂ repesents a --(CH₂)_(n)--CO--R₆ radical and R₆ represents an alkoxy, cycloalkoxy orcycloalkylalkyloxy radical can be obtained by esterification of thecorresponding derivatives of formula (III) for which R₂ represents a--(CH₂)_(n) --CO--R₆ radical and R₆ represents a hydroxyl radical.

This reaction is preferably carried out by means of an alcohol R₁₆ --OHin which R₁₆ represents an alkyl, cycloalkyl or cycloalkylalkyl radical,in the presence of tosyl chloride in pyridine, at a temperature between0° and 25° C.

The derivatives of formula (III) for which R₂ represents a --CH₂)_(n)--CO--R₆ radical and R₆ represents a phenyl radical can be obtained byreacting a corresponding derivative of formula (III) for which R₂represents a --(CH₂)_(n) --CO--R₆ radical and R₆ represents an alkoxyradical with phenylmagnesium bromide.

This reaction is preferably carried out in an inert solvent such astetrahydrofuran or diethyl ether, at a temperature between -70° C. andthe boiling point of the reaction mixture.

The compounds of formula (III) for which R₂ represents an optionallysubstituted oxazolinyl radical can be obtained by reacting acorresponding derivative of formula (III) for which R₂ represents a--(CH₂)_(n) --CO--R₆ radical, n is equal to 0 and R₆ represents ahydroxyl radical with 2-aminoethanol optionally substituted by one ormore alkyl radicals.

This reaction is carried out in an inert solvent such as toluene, thewater formed being removed, at the boiling point of the reactionmixture.

The compounds of formula (III) for which R₂ represents a3-alkyloxadiazolyl radical can be obtained by reacting a correspondingderivative of formula (III) for which R₂ represents a --CH₂)_(n)--CO--R₆ radical, n is equal to 0 and R₆ represents an alkoxy radicalwith an alkaylamidoxime.

This reaction is carried out in an inert solvent such astetrahydrofuran, in the presence of sodium hydride, at a temperaturebetween 25° C. and the boiling point of the reaction mixture.

The derivatives of formula (III) for which R₂ represents a --(CH₂)_(n)--CO--R₆ chain and R₆ represents an --NR₉ R₁₀ radical can be obtained byreacting a corresponding derivative of formula (III) for which R₆represents a hydroxyl radical, or a reactive derivative of this acid,with an amine of formula HNR₉ R₁₀.

When the acid is used, the reaction is carried out in the presence of acondensing agent used in peptide chemistry, such as a carbodiimide (forexample N,N'-dicyclohexylcarbodiimide) or N,N'-carbonyldiimidazole, inan inert solvent such as an ether (tetrahydrofuran or dioxane, forexample), an amide (N,N-dimethylformamide) or a chlorinated solvent(methylene chloride, 1,2-dichloroethane or chloroform, for example), ata temperature between 0° C. and the reflux temperature of the reactionmixture.

When a reactive derivative of the acid is used, it is possible to reactthe anhydride, a mixed anhydride or an ester (which can be chosen fromthe activated or non-activated esters of the acid).

The reaction is then carried out either in an organic medium, optionallyin the presence of an acid-acceptor such as a nitrogenous organic base(trialkylamine, pyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene or1,5-diazabicyclo[4.3.0]non-5-ene, for example), in a solvent such asmentioned above or a mixture of these solvents, at a temperature between0° C. and the reflux temperature of the reaction mixture, or in atwo-phase aqueous-organic medium in the presence of an alkali metal oralkaline-earth metal base (sodium hydroxide, potassium hydroxide) or analkali metal or alkaline-earth metal carbonate or bicarbonate at atemperature between 0° and 40° C.

The anilines, substituted where appropriate, are available on the marketor can be obtained by application or adaptation of the methods describedby R. SCHROTER, Methoden der organischen Chemie, Houben Weil, VolumeXI/1, p 360; G. J. ESSELEN et al., J. Am. Chem. Soc., 36, 322 (1914); G.ADRIANT et al., Bull. Soc. Chim. Fr., 1511 (1970); W. A. JACOBS et al.,J. Am. Chem. Soc., 39, 2418 (1917) and J. Am. Chem. Soc., 39, 1435(1917) and in the examples.

The compounds of formula (I) for which R₅ represents a phenylaminoradical in which the phenyl ring is optionally substituted by one ormore substituents chosen from halogen atoms and alkyl, alkoxy,alkylthio, trifluoromethyl, nitro, acyl, cyano, sulphamoyl,alkoxycarbonyl, carbamoyl, alkoxyiminoalkyl, alkoxyaminocarbonyl,--alk--O--CO--alk, --CH═CH--alk', --alk--O--alk,trifluoromethylsulphonamido, --alk--SO₃ H (in salt form),--O--alk--COOX, --CH═CH--COOX, --CO--COOX, --S--alk--COOX,--SO--alk--COOX, --SO₂ --alk--COOX, --O--CH₂ --alk'-COOX,--CX═N--O--alk--COOX, --alk--COOX or --alk'-COOX radicals in which X isother than a hydrogen atom can also be prepared by reacting a derivativeof formula (II) with a phenyl isocyanate in which the phenyl ring isoptionally substituted by one or more substituents chosen from halogenatoms and alkyl, alkoxy, alkylthio, trifluoromethyl, nitro, acyl, cyano,sulphamoyl, alkoxycarbonyl, carbamoyl, alkoxyiminoalkyl,alkoxyaminocarbonyl, --alk--O-CO--alk, --CH═CH--alk', --alk--O--alk,trifluoromethylsulphonamido, --alk--SO₃ H (in salt form),--O--alk--COOX, --CH═CH--COOX, --CO--COOX, --S--alk--COOX,--SO--alk--COOX, --SO₂ --alk--COOX, --O--CH₂ --alk'-COOX,--CX═N-O--alk--COOX, --alk--COOX or --alk'-COOX radicals in which X isother than a hydrogen atom.

This reaction is generally carried out in an inert solvent such astetrahydrofuran, N,N-dimethylformamide, a chlorinated solvent(chloroform or 1,2-dichloroethane, for example) or an aromatic solvent(benzene or toluene, for example), at a temperature between 10° C. andthe boiling point of the solvent.

The phenyl isocyanates are available on the market or can be obtained byapplication or adaptation of the methods described by R. RICHTER et al.,The Chemistry of Cyanate and their Thio Derivatives, S. PATAI, Part 2,Wiley, New York (1977) and in the examples.

The compounds of formula (I) for which R₅ represents a naphthyl,indolyl, quinolyl or optionally substituted phenyl radical can beprepared by reaction of a derivative of formula (II) with an acid offormula HOOC-R₅ in which R₅ has the same meanings as above, or areactive derivative of this acid.

When the acid is used, the reaction is carried out in the presence of acondensing agent used in peptide chemistry, such as a carbodiimide (forexample N,N'-dicyclohexylcarbodiimide) or N,N'-carbonyldiimidazole, inan inert solvent such as an ether (tetrahydrofuran or dioxane, forexample), an amide (dimethylformamide) or a chlorinated solvent(methylene chloride, 1,2-dichloroethane or chloroform, for example), ata temperature between 0° C. and the reflux temperature of the reactionmixture.

When a reactive derivative of the acid is used, it is possible to reactthe anhydride, a mixed anhydride or an ester (which can be chosen fromthe activated or non-activated esters of the acid).

The reaction is then carried out either in an organic medium, optionallyin the presence of an acid-acceptor such as a nitrogenous organic base(trialkylamine, pyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene or1,5-diazabicyclo[4.3.0]non-5-ene, for example), in a solvent such asmentioned above or a mixture of these solvents, at a temperature between0° C. and the reflux temperature of the reaction mixture, or in atwo-phase aqueous-organic medium in the presence of an alkali metal oralkaline-earth metal base (sodium hydroxide, potassium hydroxide) or analkali metal or alkaline-earth metal carbonate or bicarbonate at atemperature between 0° and 40° C.

The compounds of formula (I) for which R₅ represents a phenylaminoradical in which the phenyl ring is substituted by a carboxyl,--alk--COOH, --O--alk--COOH, --alk'-COOH, --CH═CH--COOH, --CO--COOH,--S--alk--COOH, --SO--alk--COOH, --SO₂ --alk--COOH, --C(═NOH)-COOH,--O--CH₂ --alk'-COOH or --CX═N-O--alk--COOH radical and/or R₂ representsa --(CH₂)_(n) -COOH chain can also be prepared by hydrolysis or,according to the situation, hydrogenolysis of the corresponding estersof formula (I).

When the alkyl or phenylalkyl esters are used, it is advantageous tocarry out the hydrolysis by means of a base such as sodium hydroxide,potassium hydroxide or lithium hydroxide, in an inert solvent such astetrahydrofuran, dioxane, water, methanol or a mixture of thesesolvents, at a temperature between 20° C. and 40° C. When phenylalkylesters are used, it is can also be advantageous to carry out ahydrogenolysis by means of hydrogen or ammonium formate in the presenceof a catalyst such as palladium on charcoal in a solvent such asmethanol or ethyl acetate. When tert-butyl esters are used, it isadvantageous to carry out the hydrolysis by means of an acid such astrifluoroacetic acid.

The compounds of formula (I) for which R₅ represents a phenylaminoradical in which the phenyl ring is substituted by a hydroxyiminoalkylor alkoxyiminoalkyl radical can also be prepared by reacting thecorresponding acylated derivative of formula (I) with a derivative offormula:

    H.sub.2 N--OR.sub.18                                       (XIV)

in which R₁₈ represents a hydrogen atom or an alkyl radical.

This reaction is generally carried out in an inert solvent such as analcohol (methanol or ethanol, for example), water or a mixture of thesesolvents, at the boiling point of the solvent and optionally in thepresence of a base such as pyridine.

The compounds of formula (I) for which R₂ represents a --(CH₂)_(n)--CO--R₆ chain, R₆ not being a hydroxyl radical, and R₅ represents anaphthyl, indolyl, quinolyl or optionally substituted phenyl radical ora phenylamino radical in which the phenyl ring is optionally substitutedby one or more substituents chosen from halogen atoms and alkyl, alkoxy,alkylthio, trifluoromethyl, nitro, acyl, cyano, sulphamoyl,alkoxycarbonyl, carbamoyl, alkoxyiminoalkyl, alkoxyaminocarbonyl,--alk--O-CO--alk, --CH═CH--alk', --alk--O--alk,trifluoromethylsulphonamido, --alk--SO₃ H (in salt form),--O--alk--COOX, --CH═CH--COOX, --CO--COOX, --S--alk--COOX,--SO--alk--COOX, --SO₂ --alk--COOX, --O--CH₂ --alk'-COOX,--CX═N-O--alk--COOX, --alk--COOX or --alk'-COOX radicals in which X isother than a hydrogen atom can also be prepared by reacting a derivativeof formula (IV) with an acid of formula: ##STR14## in which R₅ has thesame meanings as above, or a reactive derivative of this acid, and R₄has the same meanings as in the formula (I).

This reaction is preferably carried out in the presence of a condensingagent used in peptide chemistry, such as a carbodiimide, in a solventsuch as acetonitrile, tetrahydrofuran or a chlorinated solvent, or bymeans of thionyl chloride in dichloromethane at a temperature between10° C. and the boiling point of the solvent.

The acids of formula (XV) can be obtained by application or adaptationof the method described by J. R. JOHNSON et al., J. Am. Chem. Soc., 69,2370 (1947) or, for the compounds for which R₅ represents an optionallysubstituted phenylamino radical, by reacting a phenyl isocyanate inwhich the phenyl ring is optionally substituted by one or moresubstituents chosen from halogen atoms and alkyl, alkoxy, alkylthio,trifluoromethyl, nitro, acyl, cyano, sulphamoyl, alkoxycarbonyl,carbamoyl, alkoxyiminoalkyl, alkoxyaminocarbonyl, --alk--O-CO--alk,--CH═CH--alk', --alk--O--alk, trifluoromethylsulphonamido, --alk--SO₃ H(in salt form), --O--alk--COOX, --CH═CH--COOX, --CO--COOX,--S--alk--COOX, --SO--alk--COOX, --SO₂ --alk--COOX, --O--CH₂--alk'-COOX, --CX═N-O--alk--COOX, --alk--COOX or --alk'-COOX radicals inwhich X is other than a hydrogen atom with a derivative of formula:##STR15## in which R₄ has the same meanings as in the formula (I).

This reaction is generally carried out in aqueous solution in thepresence of a base such as an alkali metal bicarbonate or in aqueousdioxane at a temperature in the region of 20° C.

It is understood, for a person skilled in the art that, the use of theprocesses according to the invention described above it may benecessary, in order to prevent side reactions, to introduce protectivegroups for the amine, alcohol, acid or ketone groups, such as thosedescribed by T. W. GREENE, Protective Groups in Organic Synthesis, JohnWiley and Sons, New York. For example, the amine groups can be blockedin the form of tert-butyl or methyl carbamates, then regenerated bymeans of iodotrimethylsilane or of benzyl carbamates and thenregenerated by hydrogenation after the process according to theinvention has been carried out. The alcohol groups can, for example, beblocked in the form of a benzoate and then regenerated by hydrolysis inan alkaline medium after the process according to the invention has beencarried out. The ketone groups can be blocked in the form of a1,3-dioxolane and then regenerated by means of a hydrochloricacid/acetic acid mixture.

The enantiomers of the compounds of formula (I) containing at least oneasymmetric site can be obtained by resolution of the racemates, forexample by chromatography on a chiral column, or by synthesis fromchiral precursors.

The compounds of formula (I) can be purified by standard known methods,for example by crystallization, chromatography or extractions.

The compounds of formula (I) containing a basic residue can optionallybe converted to addition salts with an inorganic or organic acid byreacting with such an acid in an organic solvent such as an alcohol, aketone, an ether or a chlorinated solvent.

The compounds of formula (I) containing an acid residue can optionallybe converted to metal salts or to addition salts with nitrogenous basesaccording to methods known per se. These salts can be obtained byreacting a metal base (alkali metal or alkaline-earth metal base, forexample), ammonia, an amine or a salt of an amine with a compound offormula (I) in a solvent. The salt formed is separated by standardmethods.

These salts also form part of the invention.

Mention may be made, as examples of pharmaceutically acceptable salts,of the addition salts with inorganic or organic acids (such as acetate,propionate, succinate, benzoate, fumarate, maleate, oxalate,methanesulphonate, isethionate, theophyllineacetate, salicylate,methylenebis(β-hydroxynaphthoate), hydrochloride, sulphate, nitrate andphosphate), the salts with alkali metals (sodium, potassium or lithium)or with alkaline-earth metals (calcium or magnesium), the ammonium saltand the salts of nitrogenous bases (ethanolamine, trimethylamine,methylamine, benzylamine, N-benzyl-β-phenethylamine, choline, arginine,leucine, lysine or N-methylglucamine).

The compounds of formula (I) have advantageous pharmacologicalproperties. These compounds have a strong affinity for cholecystokinin(CCK) receptors and gastrin receptors and are thus useful in thetreatment and prevention of disorders linked to CCK and to gastrinaffecting the nervous system and the gastrointestinal system.

These compounds can therefore be used for the treatment or prevention ofpsychoses, of anxiety disorders, of depression, of neurodegeneration, ofpanic attacks, of Parkinson's disease, of tardive dyskinesia, ofirritable bowel syndrome, of acute pancreatitis, of ulcers, of disordersof intestinal motility, of certain tumours sensitive to CCK, as appetiteregulators, in weaning from chronic treatments and alcohol or medicinalabuse and as constrictors of the pupil of the eye.

These compounds also have a potentiating effect on the analgesicactivity of narcotic and non-narcotic medicaments. They can additionallyhave an analgesic effect of their own.

Moreover, the compounds having a strong affinity for CCK receptorsmodify memorizing capacity. These compounds can consequently beeffective in memory disorders.

The affinity of the compounds of formula (I) for CCK receptors wasdetermined according to a technique based on that of A. SAITO et al. (J.Neuro. Chem., 37, 483-490 (1981)) in the cerebral cortex and in thepancreas.

In these tests, the IC₅₀ of the compounds of formula (I) is generallyless than or equal to 1000 nM.

Moreover, it is known that products which recognize the centralreceptors of CCK have a similar specificity for the gastrin receptors inthe gastrointestinal tract (BOCK et al., J. Med. Chem., 32, 16-23(1989); REYFELD et al., Am. J. Physiol., 240, G255-266 (1981); BEINFELDet al., Neuropeptides, 3, 411-427 (1983).

The compounds of formula (I) have low toxicity. Their subcutaneous LD₅₀in mice is generally greater than 40 mg/kg.

The compounds of formula (I) for which R represents a hydrogen atom oran alkyl or phenyl radical, R₁ represents an alkyl or phenyl radical, R₂represents a --(CH₂)_(n) --CO-R₆ chain, R₃ represents a hydrogen atom oran alkyl radical, R₄ represents an alkyl radical, R₅ represents aphenylamino radical in which the phenyl ring is substituted by acarboxyl radical, R₆ represents an alkoxy radical and n is equal to 0,their salts and their isomers are particularly advantageous.

The following compounds, their salts and their isomers are particularlyadvantageous:(S)-3-3-2-(2-tert-butoxycarbonyl-5,5-diphenyl-1-pyrrolidinyl)-2-oxoethyl]ureido}benzoicacid,(2S,5R)-3-3-2-(2-tert-butoxycarbonyl-5-methyl-5-phenyl-1-pyrrolidinyl)-2-oxoethyl]ureido}benzoicacid,(2RS,5SR)-3-3-2-(2-tert-butoxycarbonyl-2-methyl-5-phenyl-1-pyrrolidinyl)-2-oxoethyl]ureido}benzoicacid,(2S,5S)-3-3-2-(2-tert-butoxycarbonyl-5-butyl-1-pyrrolidinyl)-2-oxoethyl]ureido}benzoicacid.

The examples which follow illustrate the invention without limiting it.

EXAMPLE 1

A To a solution of 2 g of tert-butyl(S)-1-{2-[3-(3-(benzyloxycarbonyl)phenyl)ureido]acetyl}-5,5-diphenylpyrrolidine-2-carboxylatein 100 cm³ of ethyl acetate, there is added 0.2 g of 10%palladium-on-charcoal. The suspension is stirred for twenty hours at atemperature in the region of 20° C. under a hydrogen atmosphere (130kPa). The catalyst is separated by filtration through Celite and rinsedwith 50 cm³ of ethyl acetate and the filtrate is concentrated to drynessunder reduced pressure. The residue is chromatographed on silica[eluent: dichloromethane/methanol (90/10 by volume)]. The fractionscontaining the expected product are combined and concentrated underreduced pressure. The residue is resuspended in 10 cm³ of diisopropylether, filtered off and dried under vacuum at a temperature in theregion of 40° C. There is thus obtained 0.65 g of(S)-3-3-2-(2-tert-butoxycarbonyl-5,5-diphenyl-1-pyrrolidinyl)-2-oxoethyl]ureido}benzoicacid melting at 180° C.; Rf=0.22 [TLC on silica, eluent:dichloromethane/methanol (90/10 by volume)].

B tert-Butyl(S)-1-{2-[3-(3-(benzyloxycarbonyl)phenyl)ureido]acetyl}-5,5-diphenylpyrrolidine-2-carboxylatecan be obtained in the following way: to a solution of 2.8 g oftert-butyl(S)-5,5-diphenyl-1-(2-phthalimidoacetyl)pyrrolidine-2-carboxylate in 50cm³ of dichloromethane, there is added, at a temperature in the regionof 5° C. 0.9 cm³ of methylhydrazine. The reaction mixture is maintainedat a temperature in the region of 5° C. for twenty hours and then heatedto reflux for four hours. After cooling to a temperature in the regionof 20° C. the organic phase is washed with twice 50 cm³ of water, driedover magnesium sulphate and concentrated under reduced pressure. Theresidue is diluted with 50 cm³ of tetrahydrofuran, then to this is added1.4 g of benzyl 3-isocyanatobenzoate. The reaction mixture is stirredfor twenty hours at a temperature in the region of 20° C. and thenconcentrated under reduced pressure. The residue is purified bychromatography on silica [eluent: cyclohexane/ethyl acetate (70/30 byvolume)]. The fractions containing the expected product are combined andconcentrated under reduced pressure. There are thus obtained 2 g oftert-butyl(S)-1-{2-[3-(3-(benzyloxycarbonyl)phenyl)ureido]acetyl}-5,5-diphenylpyrrolidine-2-carboxylatein the form of a foam, which is used as is in the subsequent syntheses.

C tert-Butyl(S)-5,5-diphenyl-1-(2-phthalimido-acetyl)pyrrolidine-2-carboxylate canbe prepared in the following way: to a solution of 1 g of tert-butyl(S)-5,5-diphenylpyrrolidine-2-carboxylate in 30 cm³ of 1,4-dioxane,there is added, at a temperature in the region of 20° C., 0.25 cm³ ofpyridine, then a solution of 0.7 g of phthaloylglycine chloride in 20cm³ of 1,4-dioxane. The reaction mixture is stirred for twenty hours ata temperature in the region of 20° C. and then concentrated underreduced pressure. The residue is dissolved in 100 cm³ of ethyl acetateand the organic phase is washed with twice 50 cm³ of distilled water,dried over magnesium sulphate and concentrated under reduced pressure.The residue is purified by chromatography on silica [eluent:cyclohexane/ethyl acetate (70/30 by volume)]. The fractions containingthe expected product are combined and concentrated under reducedpressure. There is thus obtained 1 g of tert-butyl(S)-5,5-diphenyl-1-(2-phthalimidoacetyl)pyrrolidine-2-carboxylate in theform of a foam, which is used as is in the subsequent synthesis.

D tert-Butyl (S)-5,5-diphenylpyrrolidine-2-carboxylate can be preparedin the following way: to a solution of 4.95 g of tert-butyl(S)-5-phenyl-Δ⁵ -pyrroline-2-carboxylate in 100 cm³ of tetrahydrofuran,there are added, at a temperature in the region of 0° C., 2.5 cm³ ofboron trifluoride etherate. The mixture is stirred for thirty minutes ata temperature in the region of 0° C. and then 11 cm³ of a 2M solution ofphenyllithium in an ether/hexane mixture are added over thirty minutesat a temperature in the region of -70° C. The reaction mixture isstirred for four hours at a temperature in the region of -50° C. andthen poured into 200 cm³ of a saturated aqueous ammonium chloridesolution. The aqueous phase is extracted with three times 100 cm³ ofethyl acetate. The organic extracts are combined and washed with twice100 cm³ of water, dried over magnesium sulphate and concentrated underreduced pressure. The residue is purified by chromatography on silica[eluent: petroleum ether/diethyl ether (70/30 by volume)]. The fractionscontaining the expected product are combined and concentrated underreduced pressure. There is thus obtained 1 g of tert-butyl(S)-5,5-diphenylpyrrolidine-2-carboxylate in the form of an oil, whichis used as is in the subsequent syntheses.

E tert-Butyl (S)-5-phenyl-Δ⁵ -pyrroline-2 2-carboxylate can be preparedin the following way: to a solution of 1.8 g of tert-butyl(S)-2-tert-butoxycarbonylamino-5-oxo-5-phenylpentanoate in 25 cm³ ofdichloromethane, there are added, at a temperature in the region of 20°C., 2.3 cm³ of trifluoroacetic acid. The reaction mixture is stirred forsix hours at a temperature in the region of 20° C. then 120 cm³ of asaturated aqueous sodium hydrogen carbonate solution are added. Theorganic phase is separated after settling has taken place, washed with20 cm³ of distilled water, dried over magnesium sulphate andconcentrated under reduced pressure. There is thus obtained 0.9 g oftert-butyl (S)-5-phenyl-Δ⁵ -pyrroline-2-carboxylate in the form of anoil, which is used as is in the subsequent synthesis.

F tert-Butyl (S)-2-tert-butoxycarbonylamino-5-oxo-5-phenylpentanoate canbe prepared in the following way: to a suspension of 0.72 g of magnesiumin 20 cm³ of tetrahydrofuran, there is added over thirty minutes, at atemperature between 20° and 30° C., a solution of 2.8 cm³ ofbromobenzene in 60 cm³ of tetrahydrofuran. The reaction mixture is keptstirring at a temperature in the region of 24° C. for one hundred andforty-five minutes, and is then added over twenty minutes to a solutionof 5.7 g of tert-butyl(S)-1-tert-butoxycarbonyl-5-oxopyrrolidine-2-carboxylate in 80 cm³ oftetrahydrofuran maintained at a temperature in the region of -75° C. Thereaction mixture is stirred for a further three hours at a temperaturein the region of -78° C. and then warmed to a temperature in the regionof -15° C. There are then added over fifteen minutes 100 cm³ of a 10%aqueous ammonium chloride solution. The aqueous phase is separated aftersettling has taken place and extracted with three times 100 cm³ ofdiethyl ether. The organic phases are combined and washed with twice 25cm³ of water, dried over magnesium sulphate and concentrated underreduced pressure at a temperature in the region of 50° C. The residue ispurified by recrystallization from 20 cm³ of pentane. There are thusobtained 2.5 g of tert-butyl(S)-2-tert-butoxycarbonylamino-5-oxo-5-phenylpentanoate melting at 107°C. This product can also take the form of tert-butyl(2S,5RS)-1-tert-butoxycarbonyl-5-hydroxy-5-phenylpyrrolidine-2-carboxylatemelting at 85° C.

tert-Butyl (S)-1-tert-butoxycarbonyl-5-oxo-pyrrolidine-2-carboxylate canbe obtained according to the method described by J. ACKERMANN and M.MATTHES, Helv. Chim. Acta, 73, 122-132, (1990).

G Benzyl 3-isocyanatobenzoate can be prepared in the following way: to asuspension of 2 g of charcoal in a mixture of 12.5 cm³ oftrichloromethyl chloroformate and 50 cm³ of toluene, there is added overfifteen minutes, at a temperature in the region of -25° C., a solutionof benzyl 3-aminobenzoate in 150 cm³ of toluene, prepared byneutralizing 27 g of benzyl 3-aminobenzoate hydrochloride with 14.4 cm³of triethylamine in 150 cm³ of toluene and filtering the suspension thusobtained. The reaction mixture is stirred at a temperature in the regionof 25° C. for two hours, then heated at a temperature in the region of110° C. for two hours. After cooling to a temperature in the region of25° C. the reaction mixture is degassed by bubbling nitrogen through it,filtered through filter paper and concentrated under reduced pressure ata temperature in the region of 52° C. There are thus obtained 27 g ofbenzyl 3-isocyanatobenzoate in the form of an oil, which is used as isin the subsequent syntheses.

Benzyl 3-aminobenzoate can be prepared according to the method describedby H. A. SHONLE et al., J. Amer. Chem. Soc., 43, 361 (1921).

Phthaloylglycine chloride can be prepared according to the methoddescribed by W. GRASSMANN and E. SCHULTE-UERBING, Chem. Ber., 83, 244(1950).

EXAMPLE 2

A To a solution of 0.55 g of tert-butyl(2S,5R)-1-{2-[3-(3-(benzyloxycarbonyl)phenyl)ureido]acetyl}-5-methyl-5-phenylpyrrolidine-2-carboxylatein 100 cm³ of ethyl acetate, there is added 0.05 g of 10%palladium-on-charcoal. The suspension is stirred for 20 hours at atemperature in the region of 20° C. under a hydrogen atmosphere (130kPa). The catalyst is separated by filtration through Celite and rinsedwith 50 cm³ of ethyl acetate and the filtrate is concentrated to drynessunder reduced pressure. The residue is chromatographed on silica[eluent: dichloromethane/methanol (90/10 by volume)]. The fractionscontaining the expected product are combined and concentrated underreduced pressure. The residue is resuspended in 10 cm³ of petroleumether, filtered off and dried under vacuum at a temperature in theregion of 40° C. There is thus obtained 0.3 g of(2S,5R)-3-3-2-(2-tert-butoxycarbonyl-5-methyl-5-phenyl-1-pyrrolidinyl)-2-oxoethyl]ureido}benzoicacid; Rf=0.16 [TLC on silica, eluent:dichloromethane/methanol (90/10 byvolume)].

B tert-Butyl(2S,5R)-1-{2-[3-(3-(benzyloxycarbonyl)phenyl)ureido]acetyl}-5-methyl-5-phenylpyrrolidine-2-carboxylatecan be prepared in the following way: to a solution of 0.5 g oftert-butyl (2S,5R)-5-methyl-5-phenylpyrrolidine-2-carboxylate and 0.63 gof 2-{3-[3-(benzyloxycarbonyl)phenyl]ureido}acetic acid in 50 cm³ ofacetonitrile, there is added, at a temperature in the region of 20° C.0.4 g of N,N'-dicyclohexylcarbodiimide. The reaction mixture is stirredfor twenty hours at a temperature in the region of 20° C., concentratedunder reduced pressure, taken up in 25 cm³ of ethyl acetate, filteredand rinsed with 5 cm³ of ethyl acetate. The filtrate is concentratedunder reduced pressure and the residue purified by chromatography onsilica [eluent: cyclohexane/ethyl acetate (70/30 by volume)]. Thefractions containing the expected product are combined and concentratedunder reduced pressure. There is thus obtained 0.55 g of tert-butyl(2S,5R)-1-{2-[3-(3-(benzyloxycarbonyl)phenyl)ureido]acetyl}-5-methyl-5-phenylpyrrolidine-2-carboxylatein the form of a foam, which is used as is in the subsequent syntheses.

C tert-Butyl (2S,5R)-5-methyl-5-phenylpyrrolidine-2-carboxylate can beprepared as described in Example 1 D, but starting from 4.35 g oftert-butyl (S)-5-phenyl-Δ⁵ -pyrroline-2-carboxylate, 2.5 cm³ of borontrifluoride etherate and 13.75 cm³ of a 1.6M solution of methyllithiumin diethyl ether, in 100 cm³ of tetrahydrofuran. After treatment, thereis obtained 0.5 g of tert-butyl(2S,5R)-5-methyl-5-phenylpyrrolidine-2-carboxylate in the form of anoil, which is used as is in the subsequent syntheses.

D 2-{3-[3-(Benzyloxycarbonyl)phenyl]ureido}acetic acid can be preparedin the following way: to a solution of 3.97 g of glycine and 14.62 g ofpotassium carbonate in 90 cm³ of water, there is added over fifteenminutes 13.4 g of benzyl 3-isocyanatobenzoate in solution in 70 cm³ of1,4-dioxane. The reaction mixture is stirred for four hours at atemperature in the region of 20° C., then acidified to pH 1 with a 4Naqueous hydrochloric acid solution. The insoluble product is separatedby filtration, washed with three times 50 cm³ of water and air-dried.There are thus obtained 13 g of2-{3-[3-(Benzyloxycarbonyl)phenyl]ureido}acetic acid, which is used asis in the subsequent syntheses.

EXAMPLE 3

A The reaction is carried out in a way similar to that described inExample 1A but starting from 0.54 g of tert-butyl(2RS,5SR)-1-{2-[3-(3-(benzyloxycarbonyl)phenyl)ureido]acetyl}-2-methyl-5-phenyl-pyrrolidine-2-carboxylateand 0.15 g of 10% palladium-on-charcoal in 30 cm³ of ethyl acetate.After treatment, there is obtained 0.25 g of(2RS,5SR)-3-3-2-(2-tert-butoxycarbonyl-2-methyl-5-phenyl-1-pyrrolidinyl)-2-oxoethyl]ureido}benzoicacid melting at 150° C.

B tert-Butyl(2RS,5SR)-1-{2-[3-(3-(benzyloxycarbonyl)phenyl)ureido]acetyl}-2-methyl-5-phenylpyrrolidine-2-carboxylatecan be prepared as described in Example 2 B, but starting from 0.80 g oftert-butyl (2RS,5SR)-2-methyl-5-phenylpyrrolidine-2-carboxylate, 1.0 gof 2-{3-[3-(benzyloxycarbonyl)phenyl]ureido}acetic acid and 0.63 g ofN,N'-dicyclohexylcarbodiimide in 25 cm³ of acetonitrile. Aftertreatment, there is obtained 0.6 g of tert-butyl(2RS,5SR)-1-{2-[3-(3-(benzyloxycarbonyl)phenyl)ureido]acetyl}-2-methyl-5-phenylpyrrolidine-2-carboxylatein the form of an oil, which is used as is in the subsequent syntheses.

C tert-Butyl (2RS,5SR)-2-methyl-5-phenylpyrrolidine-2-carboxylate can beprepared in the following way: to a suspension of 5.0 g of tert-butyl(RS)-2-methyl-5-phenyl-Δ⁵ -pyrroline-2-carboxylate in a mixture of 15cm³ of ethanol and 7.5 cm³ of distilled water, there is added, at atemperature in the region of 5° C., a solution of 0.76 g of sodiumborohydride and 0.35 g of sodium carbonate in 5 cm³ of distilled water.The mixture is stirred for sixty hours at a temperature in the region of20° C. and is then diluted with 150 cm³ of distilled water. The aqueousphase is extracted with twice 100 cm³ of dichloromethane and thecombined extracts are washed with 50 cm³ of distilled water, dried overmagnesium sulphate and concentrated under reduced pressure. The residueis purified by chromatography on silica [eluent: dichloromethane, thendichloromethane/methanol (99/1 by volume)]. The fractions containing theexpected product are combined and concentrated under reduced pressure.There is thus obtained 0.9 g of tert-butyl(2RS,5SR)-2-methyl-5-phenylpyrrolidine-2-carboxylate in the form of anoil, which is used as is in the subsequent synthesis.

D tert-Butyl (RS)-2-methyl-5-phenyl-Δ⁵ -pyrroline-2-carboxylate can beobtained in the following way: to a suspension of 1.6 g of 50% sodiumhydride in petroleum jelly in 50 cm³ of tetrahydrofuran, there is addeddropwise a solution of 7.5 g of tert-butyl (S)-5-phenyl-Δ⁵-pyrroline-2-carboxylate in 150 cm³ of tetrahydrofuran. The mixture isstirred for four hours at a temperature in the region of 25° C. and 2.05cm³ of methyl iodide are then added. The reaction mixture is stirred foreighteen hours at a temperature in the region of 25° C. and then 5 cm³of distilled water are added. The mixture is concentrated under reducedpressure and diluted with 200 cm³ of a 15% aqueous sodium chloridesolution. The aqueous phase is extracted with three times 100 cm³ ofdichloromethane. The organic extracts are combined and washed with twice100 cm³ of distilled water, dried over magnesium sulphate while treatingwith 3S charcoal and concentrated under reduced pressure. There are thusobtained 5.1 g of tert-butyl (RS)-2-methyl-5-phenyl-Δ⁵-pyrroline-2-carboxylate in the form of an oil, which solidifies and isused as is in the subsequent syntheses.

EXAMPLE 4

A The reaction is carried out in a way similar to that described inExample 1 A, but starting from 2.4 g of tert-butyl(2S,5S)-1-2-3-(3-(benzyloxycarbonyl)phenyl)ureido]acetyl}-5-butylpyrrolidine-2-carboxylateand 0.25 g of 10% palladium-on-charcoal in 100 cm³ of ethanol. Aftertreatment, there is obtained 1 g of(2S,5S)-3-3-2-(2-tert-butoxycarbonyl-5-butyl-1-pyrrolidyl)-2-oxoethyl]ureido}benzoicacid; [α]_(D) ²⁰ =38.4° (c=10; methanol):

B tert-Butyl(2S,5S)-1-{2-[3-(3-(benzyloxycarbonyl)phenyl)ureido]acetyl}-5-butylpyrrolidine-2-carboxylatecan be prepared as described in Example 2 B, but from 1.15 g oftert-butyl (2S,5S)-5-butylpyrrolidine-2-carboxylate, 1.65 g of2-{3-[3-(benzyloxycarbonyl)phenyl]ureido}acetic acid and 1.05 g ofN,N'-dicyclohexylcarbodiimide in 25 cm³ of acetonitrile. Aftertreatment, there are obtained 2.4 g of tert-butyl(2S,5S)-1-{2-[3-(3-(benzyloxycarbonyl)phenyl)ureido]acetyl}-5-butylpyrrolidine-2-carboxylatein the form of a foam, which is used as is in the subsequent syntheses.

C tert-Butyl (2S,5S)-5-butylpyrrolidine-2-carboxylate can be prepared inthe following way: to a solution of 1.3 g of tert-butyl (S)-5-butyl-Δ⁵-pyrroline-2-carboxylate in 50 cm³ of ethanol, there is added 0.05 g ofplatinum oxide. The suspension is stirred for twenty hours at atemperature in the region of 20° C. under a hydrogen atmosphere (130kPa). The catalyst is separated by filtration through Celite and rinsedwith 50 cm³ of ethanol and the filtrate is concentrated to dryness underreduced pressure. There are thus obtained 1.2 g of tert-butyl(2S,5S)-5-butylpyrrolidine-2-carboxylate in the form of an oil, which isused as is in the subsequent syntheses.

D tert-Butyl (S)-5-butyl-Δ⁵ -pyrroline-2-carboxylate can be prepared asdescribed in Example 1 E, but starting from 2 g of tert-butyl(S)-2-tert-butoxycarbonylamino-5-oxononanoate and 2.65 cm³ oftrifluoroacetic acid in 75 cm³ of chloroform. After treatment, there isobtained 0.6 g of tert-butyl (S)-5-butyl-Δ⁵ -pyrroline-2-carboxylate inthe form of an oil, which is used as is in the subsequent syntheses.

E tert-Butyl (S)-2-tert-butoxycarbonylamino-5-oxononanoate can beprepared in the following way: to a mixture of 9.6 cm³ of a 2.5Msolution of butyllithium in hexanes and 10 cm³ of tetrahydrofuran, thereis added over thirty minutes, at a temperature in the region of -50° C.,a solution of 5.71 g of tert-butyl(S)-1-tert-butoxycarbonyl-5-oxopyrrolidine-2-carboxylate in 30 cm³ oftetrahydrofuran. The reaction mixture is stirred for a further eighthours at a temperature in the region of -50° C. then warmed to atemperature in the region of 20° C. and stirred for sixteen hours. Themixture is then poured into 100 cm³ of a saturated aqueous ammoniumchloride solution. The aqueous phase is extracted with twice 50 cm³ ofethyl acetate. The organic phases are combined, washed with twice 50 cm³of distilled water, dried over magnesium sulphate and concentrated underreduced pressure. The residue is purified by chromatography on silica[eluent: cyclohexane/ethyl acetate (70/30 by volume)]. The fractionscontaining the expected product are combined and concentrated underreduced pressure. There are thus obtained 2 g of tert-butyl(S)-2-tert-butoxycarbonylamino-5-oxononanoate in the form of an oil,which is used as is in the subsequent syntheses.

EXAMPLE 5

A The reaction is carried out in a way similar to that described inExample 1 A, but starting from 1.65 g of tert-butyl(2S,5R)-1-{2-[3-(3-(benzyloxycarbonyl)phenyl)ureido]acetyl}-5-isobutylpyrrolidine-2-carboxylateand 0.25 g of 10% palladium-on-charcoal in 50 cm³ of ethanol. Aftertreatment, there is obtained 0.57 g of(2S,5R)-3-3-2-(2-tert-butoxycarbonyl-5-isobutyl-1-pyrrolidinyl)-2-oxoethyl]ureido}benzoicacid, the optical rotation of which is [α]_(D) ²⁰ =-36.8° (c=1.0;methanol).

B tert-Butyl(2S,5R)-1-{2-[3-(3-(benzyloxycarbonyl)phenyl)ureido]acetyl}-5-isobutylpyrrolidine-2-carboxylatecan be prepared as described in Example 2 B, but starting from 1.9 g oftert-butyl (2S,5R)-5-isobutylpyrrolidine-2-carboxylate, 2.75 g of2-{3-[3-(benzyloxycarbonyl)phenyl]ureido}acetic acid and 1.73 g ofN,N'-dicyclohexylcarbodiimide in 75 cm³ of acetonitrile. Aftertreatment, there are obtained 1.65 g of tert-butyl(2S,5R)-1-{2-[3-(3-(benzyloxycarbonyl)phenyl)ureido]acetyl}-5-isobutylpyrrolidine-2-carboxylatein the form of a foam used, which is as is in the subsequent syntheses.

C tert-Butyl (2S,5R)-5-isobutylpyrrolidine-2-carboxylate can be preparedas described in Example 4 C, but starting from 1.9 g of tert-butyl(S)-5-isobutyl-Δ⁵ -pyrroline-2-carboxylate and 0.2 g of platinum oxidein 50 cm³ of ethanol. After treatment, there are obtained 1.9 g oftert-butyl (2S,5R)-5-isobutylpyrrolidine-2-carboxylate in the form of anoil, which is used as is in the subsequent syntheses.

D tert-Butyl (S)-5-isobutyl-Δ⁵ -pyrroline-2-carboxylate can be preparedas described in Example 1 E, but starting from 3 g of tert-butyl(S)-2-tert-butoxycarbonylamino-7-methyl-5-oxooctanoate and 4 cm³ oftrifluoroacetic acid in 100 cm³ of chloroform. After treatment, thereare obtained 1.9 g of tert-butyl (S)-5-isobutyl-Δ⁵-pyrroline-2-carboxylate in the form of an oil, which is used as is inthe subsequent syntheses.

E tert-Butyl (S)-2-tert-butoxycarbonylamino-7-methyl-5-oxooctanoate canbe prepared as described in Example 1 F, but starting from 4.3 g oftert-butyl (S)-1-tert-butoxycarbonyl-5-oxopyrrolidine-2-carboxylate,2.12 cm³ of isobutyl bromide and 0.54 g of magnesium in 90 cm³ oftetrahydrofuran. After treatment, there are obtained 3 g of tert-butyl(S)-2-tert-butoxycarbonylamino-7-methyl-5-oxooctanoate in the form of anoil, which is used as is in the subsequent syntheses.

The medicaments according to the invention consist of a compound offormula (I) in free form or in the form of a pharmaceutically acceptablesalt, in the pure state or in the form of a composition in which it iscombined with any other pharmaceutically compatible product, which canbe inert or physiologically active. The medicaments according to theinvention can be employed orally, parenterally, rectally or topically.

As solid compositions for oral administration, tablets, pills, powders(gelatin capsules or wafer capsules) or granules can be used. In thesecompositions, the active principle according to the invention is mixedwith one or more inert diluents such as starch, cellulose, sucrose,lactose or silica, under an argon stream. These compositions can alsocomprise substances other than diluents, for example one or morelubricating agents such as magnesium stearate or talc, a colouringagent, a coating agent (dragees) or varnish.

As liquid compositions for oral administration, pharmaceuticallyacceptable solutions, suspensions, emulsions, syrups and elixirscontaining inert diluents such as water, ethanol, glycerol, vegetableoils or paraffin oil can be used. These compositions can comprisesubstances other than diluents, for example wetting, sweetening,thickening, flavouring or stabilizing substances.

The sterile compositions for parenteral administration can preferably besuspensions, emulsions or aqueous or non-aqueous solutions. Water,propylene glycol, a polyethylene glycol, vegetable oils, in particularolive oil, injectable organic esters, for example ethyl oleate, or othersuitable organic solvents can be used as solvent or vehicle. Thesecompositions can also contain adjuvants, in particular wetting,tonicity, emulsifying, dispersing and stabilizing agents. Sterilizationcan be carried out in several ways, for example by aseptic filtration,by incorporating sterilizing agents in the composition, by irradiationor by heating. They can also be prepared in the form of sterile solidcompositions which can be dissolved at the time of use in sterile wateror any other injectable sterile medium.

The compositions for rectal administration are suppositories or rectalcapsules which contain, besides the active product, excipients such ascocoa butter, semi-synthetic glycerides or poly(ethylene glycol)s.

The compositions for topical administration can be, for example, creams,lotions, eye drops, mouthwashes, nose drops or aerosols.

In human therapy, the compounds according to the invention areparticularly useful in the treatment and prevention of disorders linkedto CCK and to gastrin affecting the nervous system and thegastrointestinal system. These compounds can thus be used in thetreatment and prevention of psychoses, of anxiety disorders, ofdepression, of neurodegeneration, of panic attacks, of Parkinson'sdisease, of tardive dyskinesia, of irritable bowel syndrome, of acutepancreatitis, of ulcers, of disorders of intestinal motility, of certaintumours sensitive to CCK, of memory disorders, in weaning from chronictreatments and alcohol or medicinal abuse, as constrictors of the pupilof the eye, as analgesics, as potentiating agents of the analgesicactivity of narcotic and non-narcotic analgesic medicaments and asappetite regulators.

The doses depend on the desired effect, on the duration of treatment andon the administration route used; they are generally between 0.05 g and1 g per day orally for an adult with single doses ranging from 10 mg to500 mg of active substance.

Generally, the doctor will determine the appropriate dosage inaccordance with the age, the weight and all the other factors specificto the subject to be treated.

The following examples illustrate compositions according to theinvention:

EXAMPLE A

Hard gelatin capsules containing 50 mg of active product and which havethe following composition are prepared according to the usual technique:

    ______________________________________                                        3-3-2-(2-tert-Butoxycarbonyl-                                                                      50        mg                                             5,5-diphenyl-1-pyrrolidinyl)-                                                 2-oxoethyl]ureido)benzoic acid                                                Cellulose            18        mg                                             Lactose              55        mg                                             Colloidal silica     1         mg                                             Sodium carboxymethyl starch                                                                        10        mg                                             Talc                 10        mg                                             Magnesium stearate   1         mg                                             ______________________________________                                    

EXAMPLE B

Tablets containing 50 mg of active product and which have the followingcomposition are prepared according to the usual technique:

    ______________________________________                                        3-3-2-(2-tert-Butoxycarbonyl-5-methyl-                                                                50       mg                                           5-phenyl-1-pyrrolidinyl)-                                                     2-oxoethyl]ureido}benzoic acid                                                Lactose                 104      mg                                           Cellulose               40       mg                                           Povidone                10       mg                                           Sodium carboxymethyl starch                                                                           22       mg                                           Talc                    10       mg                                           Magnesium stearate      2        mg                                           Colloidal silica        2        mg                                           Mixture of hydroxymethylcellulose,                                                                    245      mg                                           glycerol and titanium oxide (72/3.5/24.5)                                     q.s. 1 finished film-coated tablet                                            weighing                                                                      ______________________________________                                    

EXAMPLE C

An injectable solution containing 10 mg of active product and which hasthe following composition is prepared:

    ______________________________________                                        3-3-2-(2-tert-Butoxycarbonyl-5-methyl-                                                               10       mg                                            5-phenyl-1-pyrrolidinyl)-                                                     2-oxoethyl]ureido}benzoic acid                                                Benzoic acid           80       mg                                            Benzyl alcohol         0.06     cm.sup.3                                      Sodium benzoate        80       mg                                            95% Ethanol            0.4      cm.sup.3                                      Sodium hydroxide       24       mg                                            Propylene glycol       1.6      cm.sup.3                                      Water q.s.             4        cm.sup.3                                      ______________________________________                                    

We claim:
 1. A compound of formula (I): ##STR16## in which: R representsa hydrogen atom or an alkyl, cycloalkyl or phenylalkyl radical or aphenyl radical optionally substituted by at least one substituent, saidsubstituent being a halogen atom or an alkyl or alkoxy radical,R₁represents an alkyl radical containing 1 to 12 carbon atoms in astraight or branched chain and optionally mono- or polyunsaturated, acycloalkyl radical containing 3 to 12 carbon atoms and optionally mono-or polyunsaturated, a polycycloalkyl radical containing 6 to 12 carbonatoms and optionally mono- or polyunsaturated, a phenylalkyl radical inwhich the phenyl ring is optionally substituted by at least onesubstituent, said substituent being an alkyl radical, an alkoxy radical,a halogen atom, a diphenylalkyl radical, a cinnamyl radical, a pyridylradical optionally substituted by one or more alkyl radicals, a furylradical optionally substituted by one or more alkyl radicals, a thienylradical optionally substituted by one or more alkyl radicals, a quinolylradical optionally substituted by one or more alkyl radicals, a naphthylradical optionally substituted by one or more alkyl radicals, an indolylradical optionally substituted by one or more alkyl radicals or a phenylradical optionally substituted by at least one substituent, saidsubstituent being a halogen atom or an alkyl, alkoxy, hydroxyl, nitro,amino, monoalkylamino, dialkylamino, alkoxycarbonyl, --CO--NR₇ R₈,--NH--CO--CH₃, trifluoromethyl or trifluoromethoxy radical, R₂represents a --(CH₂)_(n) --CO--R₆, --(CH₂)_(m) --O--CO--R"₆ or--(CH₂)_(m) --NR₉ R₁₀ chain, an oxazolinyl radical optionallysubstituted by one or more alkyl radicals, or a 3-alkyloxadiazolylradical, R₃ represents a hydrogen atom or an alkyl or cycloalkyl radicalor a phenylalkyl radical optionally substituted with at least onesubstituent, said substituent being a halogen atom or an alkyl or alkoxyradical, R₄ represents a hydrogen atom or an alkyl radical, R₅represents a phenyl radical optionally substituted by at least onesubstituent, said substituent being a halogen atom, or an alkyl, alkoxyor alkylthio radical, a naphthyl radical, an indolyl radical, a quinolylradical or a phenylamino radical in which the phenyl ring is optionallysubstituted by at least one substituent, said substituent being ahalogen atom or an alkyl, alkoxy, alkylthio, trifluoromethyl, carboxyl,alkoxycarbonyl, hydroxyl, nitro, amino, acyl, cyano, sulphamoyl,carbamoyl, hydroxyiminoalkyl, alkoxyiminoalkyl, hydroxyaminocarbonyl,alkoxyaminocarbonyl, 5-tetrazolyl, 5-tetrazolylalkyl,trifluoromethylsulphonamido, alkylsulphinyl, mono- or polyhydroxyalkyl,sulpho, --alk--O--CO--alk, --alk--COOX, --alk--O--alk, --alk'-COOX.--O--alk--COOX, --CH═CH--COOX, --CO--COOX, --alk--SO₃ H in salt form,--CH═CH--alk', --C(═NOH)-COOX, --S--alk--COOX, --SO--alk--COOX, --SO₂--alk--COOX, --O--CH₂ --alk'-COOX, --CX═N-O--alk--COOX,--alk--N(OH)--CO--alk, --alk--SO₂ H, --SO₂ --NH--CO--R₁₁, --SO₂--NH--SO₂ --R₁₁, --CO--NH--CO--R₁₁, --CO--NH--SO₂ --R₁₁, --B(OH)₂,--C(NH₂)═NOH, --SO₂ --NH--R₁₂, --CO--NH--R₁₂, ##STR17## or2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl radical, R₆ represents ahydroxyl, alkoxy, cycloalkyloxy, cycloalkylalkyloxy, phenyl or --NR₉ R₁₀radical, R"₆ represents an alkoxy, cycloalkyloxy, cycloalkylalkyloxy,phenyl or --NR₉ R₁₀ radical, R₇ represents a hydrogen atom or an alkylradical, a phenylalkyl radical or a phenyl radical optionallysubstituted by at least one substituent, said substituent being ahalogen atom or an alkyl, alkoxy or alkylthio radical, R₈ represents analkyl radical, a phenylalkyl radical or a phenyl radical optionallysubstituted by at least one substituent, said substituent being ahalogen atom or an alkyl, alkoxy or alkylthio radical, or else R₇ and R₈form, with the nitrogen atom to which they are attached, a saturated orunsaturated, mono- or polycyclic heterocycle containing 4 to 9 carbonatoms and at least one hetero atom, said hetero atom being O or N andoptionally substituted by one or more alkyl radicals, R₉ represents ahydrogen atom or an alkyl radical, a cycloalkylalkyl radical, acycloalkyl radical, a phenylalkyl radical or a phenyl radical optionallysubstituted by at least one substituent, said substituent being ahalogen atom or an alkyl, alkoxy or alkylthio radical, R₁₀ represents analkyl radical, a cycloalkylalkyl radical, a cycloalkyl radical, aphenylalkyl radical or a phenyl radical optionally substituted by atleast one substituent, said substituent being a halogen atom or analkyl, alkoxy or alkylthio radical, or R₉ and R₁₀ form, together withthe nitrogen atom to which they are attached, a saturated orunsaturated, mono- or polycyclic heterocycle containing 4 to 9 carbonatoms and at least one hetero atom, said hetero atom being O, N, or Sand optionally substituted by one or more alkyl radicals, R₁₁ representsan alkyl radical, a cycloalkyl radical, a trifluoromethyl radical or aphenyl radical optionally substituted by at least one substituent, saidsubstituent being a cyano, alkoxy, nitro or amino radical or a halogenatom, R₁₂ represents a 5-tetrazolyl radical, R₁₃ represents C═O or S═O,R₁₄ represents O or C═O, n is equal to 0, 1 or 2, m is equal to 1 or 2,X represents a hydrogen atom or an alkyl or phenylalkyl radical, alkrepresents an alkyl or alkylene radical, alk' represents a hydroxyalkyl,hydroxyalkylene, alkoxyalkyl or alkoxyalkylene radical, wherein n isother than 0 when R and R₃ each represent a hydrogen atom and R₁represents a pyridyl radical optionally substituted by one or more alkylradicals, a furyl radical optionally substituted by one or more alkylradicals, a thienyl radical optionally substituted by one or more alkylradicals, a quinolyl radical optionally substituted by one or more alkylradicals, a naphthyl radical optionally substituted by one or more alkylradicals, an indolyl radical optionally substituted by one or more alkylradicals or a phenyl radical optionally substituted by at least onesubstituent, said substituent being a halogen atom or an alkyl, alkoxy,hydroxyl, nitro, amino, monoalkylamino, dialkylamino, alkoxycarbonyl,--CO--NR₇ R₈, --NH--CO--CH₃, trifluoromethyl or trifluoromethoxyradical, and wherein, except when otherwise mentioned, said alkyl,alkylene and alkoxy radicals and said alkyl, alkylene and alkoxyportions of radicals contain 1 to 4 carbon atoms in a straight orbranched chain, said acyl radicals and portions of radicals contain 2 to4 carbon atoms and said cycloalkyl radicals and portions of radicalscontain 3 to 6 carbon atoms; a salt thereof or an isomer thereof whensaid salt or said isomer contains at least one asymmetric center.
 2. Acompound of formula (I) according to claim 1, wherein R₁ represents anisopropenyl, cyclohexyl, tetrahydrophenyl, cyclopentadiene,dihydrophenyl, norbornyl, adamantyl or norbornenyl radical; a saltthereof or an isomer thereof when said salt or said isomer contain atleast one asymmetric center.
 3. A compound of formula (I) according toclaim 1, wherein R₇ and R₈ form, with the nitrogen atom to which theyare attached, a hetrocycle selected from a piperidino ring optionallysubstituted by one or more alkyl radicals or a1,2.3,4-tetrahydroquinoline ring-system.
 4. A compound of formula (I)according to claim 1, wherein R₉ and R₁₀ form, with the nitrogen atom towhich they are attached, a heterocycle, said heterocycle being apiperidino, perhydro-1-azepinyl, 1,2,3,6-tetrahydro-1-pyridyl,1,2,3,4-tetrahydro-1-quinolyl, 1-pyrrolidinyl,1,2,3,4-tetrahydro-2-isoquinolyl, thiomorpholino or 1-indolinylring-system, wherein said ring systems are optionally substituted by atleast one alkyl radical.
 5. A compound of formula (I) according to claim1, wherein R represents a hydrogen atom or an alkyl or phenyl radical,R₁ represents an alkyl or phenyl radical,R₂ represents a --(CH₂)_(n)--CO--R₆ chain, R₃ represents a hydrogen atom or an alkyl radical, R₄represents an alkyl radical, R₅ represents a phenylamino radical inwhich the phenyl ring is substituted by a carboxyl radical, R₆represents an alkoxy radical and n is equal to 0; a salt thereof or anisomer thereof.
 6. A compound selectedfrom:--(S)-3-{3-[-2-(2-tert-butoxycarbonyl-5,5-diphenyl-1-pyrrolidinyl)-2-oxoethyl]ureido}benzoicacid;--(2S,5R)-3-{3-[-2-(2-tert-butoxycarbonyl-5-methyl-5-phenyl-1-pyrrolidinyl)-2-oxoethyl]ureido}benzoicacid;--(2RS,5SR)-3-{3-[-2-(2-tert-butoxycarbonyl-2-methyl-5-phenyl-1-pyrrolidinyl)-2-oxoethyl]ureido}benzoicacid;--(2S,5S)-3-{3-[-2-(2-tert-butoxycarbonyl-5-butyl-1-pyrrolidinyl)-2-oxoethyl]ureido}benzoicacid; the salts of these compounds and the isomers of these compounds.7. A process for the preparation of a compound of formula (I) as claimedin claim 1 wherein R₅ represents an optionally substituted phenylaminoradical, which comprises the steps of reacting a derivative of carbamicacid, optionally obtained in situ by reacting a derivative of carbonicacid, said reactive derivative of carbonic acid beingN,N'-carbonyldiimidazole, phosgene, diphosgene, triphosgene orp-nitrophenyl chloroformate, with a derivative of formula: ##STR18## inwhich R, R₁, R₂, R₃ and R₄ have the same meanings as in claim 1, with ananiline in which the phenyl ring is optionally substituted by at leastone substitutent, said substituent being a halogen atom or an alkyl,alkoxy, alkylthio, trifluoromethyl, carboxyl, alkoxycarbonyl, hydroxyl,nitro, amino, acyl, cyano, sulphamoyl, carbamoyl, hydroxyiminoalkyl,alkoxyiminoalkyl, hydroxyaminocarbonyl, alkoxyaminocarbonyl,5-tetrazolyl, 5-tetrazolylalkyl, trifluoromethylsulphonamido,alkylsulphinyl, mono- or polyhydroxyalkyl, sulpho, --aly-O-CO--alk,--alk--COOX, --alk--O--alk, --alk'-COOX, --O--alk--COOX, --CH═CH--COOX,--CO--COOX, --alk--SO₃ H in salt form, --CH═CH--alk', --C(═NOH)-COOX,--S--alk--COOX, --SO--alk--COOX, --SO₂ --alk--COOX, --O--CH₂--alk'-COOX, --CX═N--O--alk--COOX, --alk-N( OH)-CO--alk, --alk--SO₂ H,--SO₂ --NH--CO--R₁₁, --SO₂ --NH-SO₂ --R₁₁, --CO--NH--CO--R₁₁,--CO--NH--SO₂ --R₁₁, --B(OH)₂, --C(NH₂)═NOH, --SO₂ --NH--R₁₂,--CO--NH--R₁₂, ##STR19## or 2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylradical, and isolating the product of said reaction and optionallyconverting said isolated product to a salt.
 8. A process for thepreparation of a compound of formula (I) as claimed in claim 1, whereinR₅ represents a phenylamino radical in which the phenyl ring isoptionally substituted by at least one substituent, said substituentbeing a halogen atom or an alkyl, alkoxy, alkylthio, trifluoromethyl,nitro, acyl, cyano, sulphamoyl, alkoxycarbonyl, carbamoyl,alkoxyiminoalkyl, alkoxyaminocarbonyl, --alk--O-CO--alk, --CH═CH--alk',--alk--O--alk, trifluoromethylsulphonamido, --alk--SO₃ H (in salt form),--O--alk--COOX, CH═CH--COOX, --CO--COOX, --S--alk--COOX,--SO--alk--COOX, --SO₂ --alk--COOX, --O-CH₂ --alk'-COOX,--CX═N-O--alk--COOX, --alk--COOX or --alk'-COOX radical in which X isother than a hydrogen atom, which comprises the steps of reacting aderivative of formula: ##STR20## in which R, R₁, R₂, R₃ and R₄ have thesame meanings as in claim 1, with a phenyl isocyanate in which thephenyl ring is optionally substituted by at least one substituent, saidsubstituent being a halogen atom or an alkyl, alkoxy, alkylthio,trifluoromethyl, nitro, acyl, cyano, sulphamoyl, alkoxycarbonyl,carbamoyl, alkoxyiminoalkyl, alkoxyaminocarbonyl, --alk--O-CO--alk,--CH═CH--alk', --alk--O--alk, trifluoromethylsulphonamido, --alk--SO₃ H(in salt form), --O--alk--COOX, --CH═CH--COOX, --CO--COOX,--S--alk--COOX, --SO--alk--COOX, --SO₂ --alk--COOX, --O--CH₂--alk'-COOX, --CX═N-O--alk--COOX, --alk--COOX or alk'-COOX radical inwhich X is other than a hydrogen atom, isolating the product of saidreaction and optionally converting the isolated product to a salt.
 9. Aprocess for the preparation of a compound of formula (I) as claimed inclaim 1, wherein R₅ represents a naphthyl, indolyl, quinolyl oroptionally substituted phenyl radical, which comprises the steps ofreacting a derivative of formula: ##STR21## in which R, R₁, R₂, R₃ andR₄ have the same meanings as in claim 1, with an acid of formula HOOC-R₅in which R₅ has the same meaning as above, or a derivative of this acid,isolating the product of said reaction and optionally converting theisolated product to a salt.
 10. A process for the preparation of acompound of formula (I) as claimed in claim 1, wherein R₅ represents aphenylamino radical in which the phenyl ring is substituted by acarboxyl, --alk--COOH, --O--alk--COOH, --alk'-COOH, --CH═CH--COOH,--CH--COOH, --S--alk--COOH, --SO--alk--COOH, --SO₂ --alk--COOH,--C(═NOH)-COOH, --O--CH₂ --alk'-COOH or --CX═N-O--alk--COOH radicaland/or R₂ represents a --(CH₂)_(n) --COOH chain, which comprises thesteps of hydrolysing a corresponding ester of formula (I) or subjectinga corresponding ester of formula (I) to hydrogenolysis, isolating theproduct of said hydrolysing or hydrogenolysis step and optionallyconverting said isolated product to a salt.
 11. A process for thepreparation of a compound of formula (I) as claimed in claim 1, whereinR₅ represents a phenylamino radical in which the phenyl ring issubstituted by a hydroxyiminoalkyl or alkoxyiminoalkyl radical, whichcomprises the steps of reacting a corresponding acylated derivative offormula (I) with a derivative of formula:

    H.sub.2 N--OR.sub.18                                       (XIV)

in which R₁₈ represents a hydrogen atom or an alkyl radical, isolatingthe product of said reaction and optionally converting said isolatedproduct to a salt.
 12. A process for the preparation of a compound offormula (I) as claimed in claim 1, wherein R₂ represents a --(CH₂)_(n)--CO-R₆ chain, R₆ not being a hydroxyl radical, and R₅ represents anaphthyl indolyl, quinolyl or optionally substituted phenyl radical or aphenylamino radical in which the phenyl ring is optionally substitutedby at least one substituent, said substituent being a halogen atom or analkyl, alkoxy, alkylthio, trifluoromethyl, nitro, acyl, cyano,sulphamoyl, alkoxycarbonyl, carbamoyl, alkoxyiminoalkyl,alkoxyaminocarbonyl, --alk--O-CO--alk, --CH═CH--alk', --alk--O--alk,trifluoromethylsulphonamido, --alk--SO₃ H (in salt form),--O--alk--COOX, --CH═CH--COOX, --CO--COOX, --S--alk--COOX,--SO--alk--COOX, SO₂ --alk--COOX, --O--CH₂ --alk'-COOX,--CX═N-O--alk--COOX, --alk--COOX or--alk'-COOX radical in which X isother than a hydrogen atom, which comprises the steps of reacting aderivative of formula: ##STR22## in which R, R₁ and R₃ have the samemeanings as in claim 1 and R₂ has the same meaning as above, with anacid of: ##STR23## in which R₅ has the same meaning as above, or areactive derivative of this acid, and R₄ has the same meaning as inclaim 1, isolating the product of said reaction and optionallyconverting said isolated product to a salt.
 13. A pharmaceuticalcomposition comprising a pharmaceutically effective amount of a compoundof formula (I) according to claim 1 and a pharmaceutically acceptablecarrier.
 14. A method of treating disorders linked to cholecystokininand gastrin, which comprises administering to a host in need of saidtreatment an effective amount of a compound of formula (I) according toclaim 1.